Recombinomics
CommentaryJune 1, 2006``We have not received any
request to share it with GenBank,'' Kandun said yesterday in an
interview from Jakarta. ``If there was a request, and it's clear that
it is in the public interest to do so, why not? I would surely
recommend it to the health minister.''

``We think it's important to
share this information so that everyone can have a better understanding
of what's going on,'' said Maria Cheng, a spokeswoman for the World
Health Organization in Geneva.

The above comments from the director-general of disease control in
Indonesia as well as a spokesperson for the WHO would appear to pave
the way for the release
of H5N1 bird flu sequences sequestered at the WHO private database.
Release of these sequences is important for determining how H5N1 is
evolving in Indonesia.

The recent cluster
in north Sumatra was the largest and most deadly in Indonesia and had
clear examples of multiple human-to-human transmissions. The
description of the sequences provided information of the lack of
reassortment and "significant mutations". These significant
mutations appear to be limited to HA positions 226 and 228 in the
receptor binding domain. However, usually resistance markers for
the two classes of anti-virals are determined as well as position 627
in the PB2 gene.

The WHO report indicated the H5N1 was sensitive to neuraminidase
inhibitors, but failed to mention sensitivity to ion channel blocks,
the amantadanes. This omission suggested
the isolates were amantadane resistant with M2 S31N. The high
concentrations of H5N1 in the nose ands throat also
raised the possibility of acquisition of PB2 E627K. Moreover, the
similarity to bird isolates suggest the HA cleavage site was the wild
type sequence, RERRRKKR.

The amantadine resistance would affect treatment choices and the acquisition
of PB2 E627K may make the H5N1 more transmissible, which would account
for the size of the cluster and length of the transmission chain.

In addition to questions concerning the sequences in Sumatra, there are
additional concerns about the sequence from West Java, which have a novel
cleavage site, RESRRKKR, which has not been reported in bird
sequences anywhere. This difference between in the human and bird
sequences raises questions on the origin of infections. Since
most H5N1 testing is limited to suspect cases that have had recent
exposure to dead and dying birds, cases due to infection by H5N1 from
an alternate reservoir may be overlooked.

Publishing of the sequences allows for sophisticated analysis that can
determine the source of the infections. WHO consultants believe
H5N1 evolves via reassortment and random mutation. However,
compelling evidence indicates change via recombination is much more
common. Since acquisitions of polymorphisms are derived from
other viruses via dual infection, the acquired polymorphisms can be
used to identify donor sequences and viruses. Thus, polymorphisms
can be used to trace origins, and this tracing is most efficient when a
robust database is available.

Therefore release of the sequences allows important questions of
origins of infections to be determined. These sequestered
sequences as well as additional sequences from animal reservoirs will
aid in the identification and elimination or control of reservoirs
causing the increasing number of H5N1 infections in humans and other
hosts.